Articles for Tissue Regeneration with Biodegradable Polymer

ABSTRACT

The invention is to articles made from extracellular matrix sheets that encase biodegradable polymeric material. Methods of healing wounds or regenerating tissue at sites of defect by placing said articles in mammals are claimed. The biodegradable polymer can change quality upon contact with a physiological parameter such as temperature or pH that causes, for example, a liquid polymer to gel or harden. The degradation of the polymer can be controlled to suit a tissue regeneration or wound healing time course. Additional components such as proteins, cells and drugs can be added to the biopolymer composition.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/747,028, filed on May 10, 2007.

FIELD OF THE INVENTION

The invention relates to articles made with extracellular matrixmaterials.

BACKGROUND OF THE INVENTION

Tissue regeneration has been accomplished by using extracellular matrixmaterial derived from mammalian tissues. Some of these mammalian tissuesthat have been described in patent literature include small intestinesubmucosa (SIS), liver basement membrane (LBM), urinary bladdersubmucosa (UBS) and stomach submucosa (SS). See U.S. Pat. No. 5,554,389,U.S. Pat. No. 4,902,508, and U.S. Pat. No. 5,281,422. Enamel matrices,which are the extracellular matrix around forming teeth, are describedin U.S. Pat. No. 7,033,611. Extracellular matrices from these tissueshave been isolated and described as solid materials (sheets andparticulates), and in fluidized or emulsion forms made by reconstitutingparticulate in a suitable buffer. Presently, these extracellular matrixcompositions are used for tissue grafting, wound healing, and tissueregeneration purposes.

It would be advantageous to the field of tissue engineering to inventarticles and compositions for effecting improved tissue regeneration.

SUMMARY OF THE INVENTION

The invention is an article comprising a sheet of extracellular matrixencasing a composition comprising a biodegradable polymer.

The invention is also an article comprising a conduit formed of an outertube and a concentric inner tube, each tube comprising extracellularmatrix sheets, said conduit having a space between said outer tube andsaid inner tube, said space occupied with a composition comprising abiodegradable polymer.

The invention is further a method comprising identifying a defect orwound in tissue in a mammal, providing an article comprising a sheet ofextracellular matrix encasing a composition comprising a biodegradablepolymer, contacting said defect or wound with said article, andregenerating tissue at said defect or healing said wound, whereby saidcomposition biodegrades in said mammal at a designed rate.

These and other elements of the invention are detailed below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts an article having two sheets of extracellular matrixencasing a composition comprising biodegradable polymer;

FIG. 1B depicts an article having two sheets of extracellular matrixencasing a composition comprising a biodegradable polymer having theends of the article closed to fully encase the composition; and

FIG. 1C depicts concentric tubes forming a conduit that encases abiodegradable polymer placed between the two concentric tubes that formthe conduit.

DETAILED DESCRIPTION OF THE INVENTION

The invention is an article made of one or more extracellular matrixsheets encasing a composition comprising a biodegradable polymer. Thearticle can comprise two or more sheets of extracellular matrix. Twosheets can sandwich an amount of the composition comprising abiodegradable polymer. The invention is also an article comprisingconcentric tubes of extracellular matrix forming a conduit with a spacebetween the tubes that is filled with a biodegradable polymer.

The article of concentric tubes is useful for tissue regeneration orwound healing at a vessel in the body. The vessel can be for example ablood vessel, such as an artery or vein. The vessel can also be a largeintestine, or small intestine. The vessel can also be any number oftubes that connect to and from the organs in the body, for example, inthe reproductive organs (e.g. fallopian tubes, prostate), bladder,urinary tract, gastrointestinal tract, lung, heart and kidney vessels,and in general any tubular part of the mammalian body in need of repair.The sizes and design of the article will be adjusted for the locationthat the article is being placed in the body, thus, for example, a largeintestine will receive a large conduit, and an artery or vein a muchsmaller one.

The inventions are useful for placing in a mammal in need of tissueregeneration to effect tissue regeneration at the site of placement ofthe article or device. The extracellular matrices used in the article(i.e. the sheets of extracellular matrix) can be from one or more thanone source of extracellular matrix in a mammal, for example one sheetcan be SIS and one sheet can be SS, or both sheets (or tubes) can beSIS.

The biodegradable composition can change consistency in response to aphysiological condition. Thus, the composition outside the body can be acertain consistency (for example a liquid) and then when placed in thebody the consistency can change in response to the change in pH,temperature, or enzymatic activity present in the body at the site ofplacement of the article. Accordingly, and optimally, the compositionmight be a liquid before placement in the body and gel upon contact withthe environment in the body with the physiological condition that makesthe composition gel (e.g. pH difference, temperature difference, orenzymatic activity).

The biodegradable polymer composition can comprise an additionalelement, for example a protein, a cell, or a drug.

The article that is a conduit can be formed of an outer tube and aconcentric inner tube. Each tube can comprise extracellular matrixsheets, and the conduit can have a space between the outer tube and theinner tube. The space is occupied with a composition comprising abiodegradable polymer. As with the other articles of the invention, thecomposition between the two pieces of extracellular matrix can alsocomprise an additional component, such as a protein, a cell, or a drug.

The composition can also change consistency in response to aphysiological condition, as described earlier.

The biodegradable polymer composition in all these articles can bedesigned to degrade at a predetermined or designed rate. For example, ifit is determined that the extracellular matrix sheets that encase thebiodegradable polymer need about 3 months of support before they havemore or less fully assimilated as new tissue at the site, then thebiodegradable polymer should be designed to be fully degraded by 3months of presence in the body. The polymer composition can be adjustedto degrade at different rates depending on the polymer composition andits known rate of degradation in the body, as well as by manipulatingother factors such as the specific composition of the polymer, thequantity of polymer placed in the article, as well as by manipulatingother parameters in the composition.

The invention is also a method of using the articles of the invention.The articles can be used to generate new tissue at a site of defect, orto heal a wound in the tissue. Most commonly humans are the subjects forthis treatment, but any mammal can be treated using these methods.Mammals such as horses, dogs, cats and other mammals (particularlydomesticated mammals) in need of tissue regeneration can be treated withthese methods.

The method includes that a defect or wound in mammalian tissue isidentified in a subject mammal. An article such as described abovehaving extracellular matrix encasing a composition comprising abiodegradable polymer is provided. The defect or wound in the subjectmammal is treated by contacting the defect or wound with the article.The articles can be either a flat sandwich type configuration, encasingthe composition, or a conduit of two concentric tubes of extracellularmatrix that encase the composition between the concentric tubes, or thearticle can be some other shape suitable to the purpose of tissueregeneration or wound healing at the site. As a result of placing thearticle at the site in the mammal, tissue is regenerated at the defector the wound is healed, about which time the biodegradable polymer inthe composition has degraded or nearly degraded.

The tissue to be repaired using the articles of the invention, and themethods of the invention include myocardial tissue, pancreatic tissue,and liver tissue, for example.

As with the articles of the invention, the method invention providesthat the composition can also include an additional component, such as aprotein, cell or drug.

The article of the invention is made up of a composition comprising abiodegradable polymer. The biodegradable polymer provides support forthe extracellular matrix components of the articles and then slowlydegrades as the matrix integrates into the surrounding tissue andbecomes new tissue in the animal.

Biodegradable polymers can be either natural or synthetic. A material iscalled degradable with respect to specific environmental conditions ifit undergoes a degradation to a specific extent within a given timemeasured by specific standard test methods. Degradation is also anirreversible process leading to a significant change of structure of amaterial, typically characterized by a loss of properties (e.g.integrity, molecular weight, structure or mechanical strength) and/orfragmentation. Degradation is affected by environmental conditions andproceeds over a period of time comprising one or more steps.Disintegration is the falling apart into very small fragments ofpackaging or packaging material caused by degradation mechanism. Thegeneral criteria for selecting a polymer for use as a biomaterial is tomatch the mechanical properties and the time of degradation to the needsof the application. The ideal polymer for a particular application wouldbe configured so that it has mechanical properties that match theapplication, remaining sufficiently strong until the surrounding tissuehas healed; does not invoke an inflammatory or toxic response; ismetabolized in the body after fulfilling its purpose, leaving no trace;is easily processable into the final product form; demonstratesacceptable shelf life and is easily sterilized. Some polymers suitablefor use in the articles and devices of the invention include (but arenot limited to) the following: polyglycolide (PGA), polylactide (PLA),poly .epsilon.-caprolactone, poly dioxanone (a polyether-ester), polylactide-co-glycolide, polyamide esters, polyalkalene esters, polyvinylesters, polyvinyl alcohol, polyanhydrides, and in addition to otherpolymers under investigation for similar applications. Natural polymersthat might be used include (but are not limited to) polysaccharides(e.g. starch and cellulose), proteins (e.g. gelatin, casein, silk,wool), polyesters (e.g. polyhydroxyalkanoates), and others (e.g.lignans, shellac, natural rubber). This list is not intended to beexhaustive of all the biodegradable polymers suitable for use in thecompositions.

The encasing of the biodegradable polymer composition can beaccomplished by laminating the ends of the sheets to enclose thecomposition inside. The composition can be sandwiched between two sheetsof extracellular matrix with the edges of the sheets laminated together,or somehow made to close either fully or partially to encase thecomposition inside. The article can also be made by providing acomposition that is enclosed by a single sheet that folds over on itselfto hold the composition. The three sides of the sheet can be laminatedto itself to form an article that encases the composition and which isfolded on one edge.

The sheets can be from the same source of extracellular matrix, i.e.both or all sheets can be made of SIS from a pig. The sheets can also befrom different sources of extracellular matrix, for example the firstsheet is SIS, and the second sheet is SS. Both the SIS and SS can befrom the same species of mammal (pig) or each from a different speciesof mammal (SIS from pig, and SS from cow). Accordingly, suchextracellular matrices as LBM and UBS can be used for making the sheets,and mixed and matched according to the needs of the animal beingtreated. For example, it may be beneficial to have an underside sheet ofa higher tensile strength material such as SIS, and a topside sheet of aweaker strength such as LBM. Likewise with the concentric tubes theouter tube can be of SIS and the inner tube can be of LBM or UBS, theinner tubes providing less tensile strength but equal or greater tissueregenerative potential than the outer tube of SIS.

The sheets can be laminated to each other at the edges around an amountof composition comprising the biodegradable polymer that then becomesencased in the two sheets upon lamination of the outer sheets to eachother. The lamination of the two outer sheets together can be partial orcomplete, so that the composition inside can be entirely containedwithin the two sheets, or can be permitted to ooze out from between thesheets upon placement in the subject receiving treatment. The two sheetsmay also be attached to each other by quilting of the sheets in themiddle of the sheets much like a quilt is assembled when made of 2 ormore layers of fabric.

The composition can be a mixture of more than one biodegradable polymer.Accordingly, in between the sheets of matrix can be of mixed source ofbiodegradable polymer, so that for example a biodegradable polymercomposition can be a 50:50 mixture of PGA and PGLA, or some otherpermutations of mixtures that will serve the purpose of the compositionin the article. The biodegradable polymer can also be mixed with acertain percentage of liquid, gel or particulate extracellular matrix.The function of the composition will be to support the extracellularmatrix sheets or tubes until they have assimilated into new tissue inthe animal, and thus the strength of the composition and the rate of itsdegradation in the animal will be two of the important parameters toadjust as the composition is fine-tuned for a particular specificapplication in a particular subject being treated.

Mammalian tissue sources are in general any tissue having anextracellular matrix that can be isolated from a mammal andde-cellularized. Thus for example, most mammalian organs are tissuesources. The tissue sources can be for example any mammalian tissue,including but not limited to the small intestine, large intestine,stomach, lung, liver, kidney, pancreas, placenta, heart, bladder,prostate, tissue surrounding growing tooth enamel, tissue surroundinggrowing bone, and any fetal tissue from any mammalian organ.

The mammal from which the extracellular matrix sheets are derived can beany mammal, including (but not limited to): humans, cows, pigs, dogs,cats, horses, rodents or any other mammal who provides the necessarymaterial. Any mammal can potentially contribute extracellular matrix formaking the sheets of the invention.

The forms of the extracellular matrices that make up the articles aregenerally forms such as sheets that can be folded or manipulated to bothencase the biodegradable polymer, and form the desired shape for thearticle or device. Thus the articles or devices can form sandwiches, orconduits, or other shapes such a triangular shapes, circular shapes,irregular shapes, and shapes tailored or designed to fit specificlocations in the animal.

The sheets in the article can have any number of shapes, e.g. square,rectangular, triangular, circular, or an irregular shape. The shape ofthe article can be tailored to fit the site where the article will beintroduced into the body. Accordingly, the compositions that make up thecenter or encased portion of the article can be any of these forms,encased in one or more sheets of extracellular matrix. The form can alsobe a conduit having two concentric tubes with the space between thetubes filled with the biodegradable polymer composition. (see FIG. 1C)

The biodegradable polymer is useful to the articles and devices of theinvention because it will hold a shape and retain a presence for atemporary period of time. As the sheet of extracellular matrix form newtissue, the biopolymer will help the sheets maintain a position or shapenecessary until the tissue is formed. Ideally the degradation of thebiopolymer is designed to match the needs of the application so that thebiopolymer degrades as the new tissue is being formed, and eventually iscompletely gone by the time the new tissue is strong enough to fullysupport its new application in the body.

Extracellular matrix sheets and any incidental emulsion used in thecomposition filler can be obtained from the tissues of mammals byprocesses such as described in U.S. Pat. No. 5,554,389, U.S. Pat. No.4,902,508, and U.S. Pat. No. 5,281,422. For example, the urinary bladdersubmucosa is an extracellular matrix that has the tunica mucosa (whichincludes the transitional epithelial layer and the tunica propria), asubmucosal layer, 3 layers of muscularis, and the adventitia (a looseconnective tissue layer). This general configuration is true also forsmall intestine submucosa (SIS) and stomach submucosa (SS). Obtainingenamel matrices is described in U.S. Pat. No. 7,033,611. Enamel matrixis extracellular matrix existing near forming teeth.

Matrices can be used in whole or in part, so that for example, anextracellular matrix can contain just the basement membrane (ortransitional epithelial layer) with the sub-adjacent tunica propria, thetunica submucosa, tunica muscularis, and tunica serosa. The matrixcomposition can contain any or all of these layers, and thus couldconceivably contain only the basement membrane portion, excluding thesubmucosa, However, generally, and especially since the submucosa isthought to contain and support the active growth factors and otherproteins necessary for in vivo tissue regeneration, the matrixcomposition from any given source will contain the active extracellularmatrix portions that support cell development and differentiation andtissue regeneration once placed in a live mammal. This it is generallyunderstood by persons of skill in the art that the extracellular matrixof any of the mammalian tissue consists of several basically inseparablelayers broadly termed extracellular matrix. Where layers can beseparated these separate layers can electively be included in thecomposition, depending on whether they serve the purpose that is thegoal of the article.

Any incidental extracellular matrix used as part of the composition withthe biodegradable polymer can be made as follows. Extracellular matrixcan be made into a particulate and fluidized for use in the compositionsas described in U.S. Pat. No. 5,275,826 to Badylak, U.S. Pat. No.6,579,538 to Spievack, and U.S. Pat. No. 6,933,326 to Griffey. Fluidizedor emulsified compositions (the liquid or semi-solid forms) can bepresent at a certain concentration, for example at a concentration ofextracellular matrix greater than about 0.001 mg/ml. The concentrationof these liquid or semi-solid components of the extracellular matrixcomposition can be in a range from about 0.001 mg/ml to about 200 mg/ml.The concentrations can further be found in more specific ranges such asfor example the following set of ranges: about 5 mg/ml to about 150mg/ml, about 10 mg/ml to about 125 mg/ml, about 25 mg/ml to about 100mg/ml, about 20 mg/ml to about 75 mg/ml, about 25 mg/ml to about 60mg/ml, about 30 mg/ml to about 50 mg/ml, and about 35 mg/ml to about 45mg/ml, and about 40 mg/ml. to about 42 mg/ml. This set of ranges isexemplary and not intended to be exhaustive. It is contemplated that anyvalue within any of these specifically listed ranges is a reasonable anduseful value for a concentration of a liquid or semi-solid component ofthe composition.

The one or more sheets of extracellular matrix can comprise combinationsof forms of extracellular matrix from such sources as, for example butnot limited to, small intestine submucosa, liver basement membrane,stomach submucosa, urinary bladder submucosa, placental basementmembrane, pancreatic basement membrane, large intestine submucosa, lunginterstitial membrane, respiratory tract submucosa, heart extracellularmatrix, dermal matrix, and in general extracellular matrix from anymammalian fetal tissue. Any one of these tissue sources can provideextracellular matrix that can then be manipulated into a designated formsuch as a sandwich or a conduit.

The compositions of the invention that are encased by the sheets ofextracellular matrix can be made from a single source of biodegradablepolymer, or multiple sources. Some extracellular matrix emulsion orparticulate may also be mixed with the biodegradable polymer, althoughgenerally, the goal is to have all of the polymer disintegrate ordegrade after a suitable period of time in the body.

Depending on the number of sheets in the article or device, the articlesor devices can be made from three mammalian tissue sources, fourmammalian tissue sources, 5 mammalian tissue sources, 6 mammalian tissuesources, and conceivably up to 10 or more tissue sources. Once againthese tissue sources can be from the same mammal (for example the samecow, the same pig, the same rodent, the same human, etc.), the samespecies of mammal (e.g. a cow, a pig, a rodent, a human), or differentmammalian animals (but the same species, e.g. cow 1 and cow 2, or pig 1and pig 2), or different species of mammals (for example liver matrixfrom a pig, and small intestine submucosa from a cow, and urinarybladder submucosa from a dog). Any mammal can be a source of theextracellular matrix for these articles, accordingly, humans, cows,pigs, horses, rodents, cats, dogs, and in general any available orsuitable mammal can be a source of the required extracellular matrix forthese articles.

The articles or devices can be made entirely of one extracellularmatrix, for example of small intestine submucosa (SIS) sheets, withbiopolymer composition in between some or all of the sheets.

Turning now to the figures, FIG. 1A depicts a sandwich configuration ofthe article. Element 10 is a bottom sheet of extracellular matrix.Element 8 is a top sheet of extracellular matrix. Element 12 is thecomposition of biodegradable polymer sandwiched between sheet 8 and 10.

FIG. 1B depicts the sandwich with closed ends, the article encasing thecomposition of biodegradable polymer. Bottom sheet 10 and top sheet 8are closed or nearly closed at points 14 to encase the biodegradablepolymer composition 12.

FIG. 1C depicts concentric tubes having biopolymer in between them.Outer concentric tube 20 exists on the outside of the article.Composition having biodegradable polymer 24 is between outer tube 20 andinner concentric tube 22. Space 26 exists in the center of theconcentric tubes through which fluid or other material can pass afterthe article is placed in the body at the site where it is needed.

The composition comprising a biodegradable polymer can further includeone or more additional components to aid in some aspect of the tissueregenerative process. The additional component will generally be part ofthe composition comprising biodegradable polymer that is placed betweenthe sheets of matrix. Thus, the additional component can help toregenerate tissue, heal a wound, better recruit stem cells, manipulatethe immune environment in a beneficial way, therapeutically treat thelocal environment, or otherwise contribute to some aspect of the processfor which the composition is being used.

Thus, the additional component can be a cell, a protein or a drug (e.g.a small molecule). The cell can be a stem cell, such as, for example aof human embryonic stem cell, a fetal cardiomyocyte, a myofibroblast, amesenchymal stem cell, an autotransplanted expanded cardiomyocyte, anadipocyte, a totipotent cell, a pluripotent cell, a blood stem cell, amyoblast, an adult stem cell, a bone marrow cell, a mesenchymal cell, anembryonic stem cell, a parenchymal cell, an epithelial cell, anendothelial cell, a mesothelial cell, a fibroblast, a myofibroblast, anosteoblast, a chondrocyte, an exogenous cell, an endogenous cell, a stemcell, a hematopoetic stem cell, a pluripotent stem cell, a bonemarrow-derived progenitor cell, a progenitor cell, a myocardial cell, askeletal cell, a fetal cell, an embryonic cell, an undifferentiatedcell, a multi-potent progenitor cell, a unipotent progenitor cell, amonocyte, a cardiomyocyte, a cardiac myoblast, a skeletal myoblast, amacrophage, a capillary endothelial cell, a xenogenic cell, an allogeniccell, an adult stem cell, and a post-natal stem cell. This list is notintended to be exhaustive.

The protein can be for example a growth factor, or any other type orprotein that might stimulate some part of the tissue regenerativeprocess a collagen, a proteoglycan, a glycosaminoglycan (GAG) chain, aglycoprotein, a growth factor, a cytokine, a cell-surface associatedprotein, a cell adhesion molecule (CAM), an angiogenic growth factor, anendothelial ligand, a matrikine, a matrix metalloprotease, a cadherin,an immunoglobin, a fibril collagen, a non-fibrillar collagen, a basementmembrane collagen, a multiplexin, a small-leucine rich proteoglycan,decorin, biglycan, a fibromodulin, keratocan, lumican, epiphycan, aheparan sulfate proteoglycan, perlecan, agrin, testican, syndecan,glypican, serglycin, selectin, a lectican, aggrecan, versican, nuerocan,brevican, cytoplasmic domain-44 (CD44), macrophage stimulating factor,amyloid precursor protein, heparin, chondroitin sulfate B (dermatansulfate), chondroitin sulfate A, heparan sulfate, hyaluronic acid,fibronectin (Fn), tenascin, elastin, fibrillin, laminin,nidogen/entactin, fibulin I, fibulin II, integrin, a transmembranemolecule, platelet derived growth factor (PDGF), epidermal growth factor(EGF), transforming growth factor alpha (TGF-alpha), transforming growthfactor beta (TGF-beta), fibroblast growth factor-2 (FGF-2) (also calledbasic fibroblast growth factor (bFGF)), thrombospondin, osteopontin,angiotensin converting enzyme (ACE), and vascular epithelial growthfactor (VEGF). This list is not intended to be exhaustive.

The additional component can also be a drug, such as an agent that hastherapeutic properties. The drug can be bioactive and play some role inthe process of tissue regeneration, for example, or act as anantibiotic, antiviral, or other active therapeutic agent serving apurpose in the composition as a whole, also by example. The drug can bea small molecule, or any other agent having therapeutic properties. Thedrug can have the capacity to treat the patient locally at the site ofplacement of the article, as for example a local antibiotic oranti-inflammatory agent. The drug may also alternatively have thecapacity to treat the patient or subject systemically, as with amolecule that can travel in the blood stream from the site of placementof the article to other parts of the body where it can have effects,e.g. a therapeutic agent that can have effects in another system in thepatient.

The invention contemplates using the articles for regenerating tissue asa defect or healing a wound in mammalian tissue. The defect can be acut, disease, wound, burn, scar, necrosis, or other abnormality thatwould be beneficial to the patient to treat. Regenerating tissue at thedefect can be one response elicited from the step of placing theextracellular matrix sheets in contact with the defect, while thebiodegradable polymer can help hold a shape or support the extracellularmatrix sheet until the tissue regenerates or the wound heals. If thedefect is a wound in need of healing, wound healing may be anotherresponse that occurs as a result of placing the extracellular matrix atthe wound site. In general any term that identifies that the tissuecould benefit from healing or where the concept of tissue regenerationfits within the scope of the use for the composition can be used todescribe the process that is the goal of placing the article in thepatient.

Therapeutically effective amount is a term meant to capture the ideathat you need to apply enough of an element of the composition insufficient strength so that the composition can have a positive effecton the tissue that is being treated in the subject. Thus, the termtherapeutically effective amount applies to the additional componentsadded to the composition comprising the biodegradable polymer. The termtherapeutically effective amount may therefore apply to a quantity ofmatrix, or a size of a sheet of matrix, or a volume or weight of powder,or a concentration of liquid or emulsion. That the amount istherapeutically effective is determined by the composition's ability tohave a regenerative or wound healing effect at the site where thecomposition contacts the tissue. A therapeutically effective amount isdeterminable by routine testing in patients with wounds or defects. Ingeneral a minimal therapeutically effective amount would be consideredsufficient composition to contact amply all of the wound or defect inthe tissue.

Regenerating tissue is the ability to make tissue regrow, an organregrow itself, and for new tissue to reform without scarring. Healing awound is the ability of the tissue to heal without scarring, or withless scarring than would have occurred without the article.

All references cited are incorporated in their entirety. Although theforegoing invention has been described in detail for purposes of clarityof understanding, it will be obvious that certain modifications may bepracticed within the scope of the appended claims.

1. A method for regenerating mammalian tissue, comprising the steps of: identifying a defect site in mammalian tissue; providing an article comprising extracellular matrix (ECM) encasing a composition comprising a biodegradable polymer; and disposing said article at said tissue defect site, wherein new tissue is regenerated at said tissue defect site, and where said composition biodegrades.
 2. The method of claim 1, wherein said ECM comprises mammalian tissue selected from the group consisting of small intestine submucosa (SIS), stomach submucosa (SS), liver basement membrane (LBM) and urinary bladder submucosa (UBS).
 3. The method of claim 1, wherein said biodegradable polymer is selected from the group consisting of polyglycolide (PGA), polylactide (PLA), poly ε-caprolactone, poly dioxanone, poly lactide-co-glycolide, polyamide esters, polyalkalene esters, polyvinyl esters, polyvinyl alcohol, and polyanhydrides.
 4. The method of claim 1, wherein said article further comprises a growth factor selected from the group consisting of transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), fibroblast growth factor-2 (FGF-2) and vascular epithelial growth factor (VEGF). 